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TopBP1 mediates mutant p53 gain of function through NF-Y and p63/p73

Kang Liu1, Shiyun Ling, Weei-Chin Lin

  • 1Section of Hematology/Oncology, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.

Molecular and Cellular Biology
|September 21, 2011
PubMed

Insights

Topoisomerase II-binding protein 1 (TopBP1) drives cancer progression by mediating mutant p53 gain-of-function activities. Inhibiting TopBP1 may offer a novel therapeutic strategy for cancers with p53 mutations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Mutant p53 proteins contribute to cancer development, metastasis, and therapy resistance.
  • Mutant p53 gain-of-function is partly mediated through interactions with transcription factors like NF-Y and p63/p73.

Purpose of the Study:

  • To investigate the role of Topoisomerase II-binding protein 1 (TopBP1) in mediating mutant p53 gain-of-function activities in cancer.
  • To provide in vitro and in vivo evidence for TopBP1's involvement in cancer progression driven by mutant p53.

Main Methods:

  • Investigated interactions between TopBP1, mutant p53, NF-YA, p63/p73, and p300 using in vitro assays.
  • Analyzed the effects of TopBP1 depletion on gene expression (NF-Y and p63/p73 targets) in mutant p53 cancer cells.
  • Assessed the impact of TopBP1 on chemoresistance and tumor growth in a xenograft model.

Main Results:

  • TopBP1 interacts with mutant p53 and NF-YA, promoting recruitment of mutant p53 and p300 to NF-Y target gene promoters.
  • TopBP1 facilitates mutant p53's inhibition of p63/p73 transcriptional activity.
  • TopBP1 depletion reversed gene expression changes and sensitized cells to chemotherapy, while inhibiting tumor growth in vivo.

Conclusions:

  • TopBP1 is a key mediator of mutant p53 gain-of-function in cancer.
  • TopBP1's role in promoting tumor growth and chemoresistance highlights its potential as a therapeutic target in conjunction with mutant p53.

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